Alectinib, which is developed by the branch company of Roche in Japan, Chugai Pharmaceutical, is a new anaplastic lymphoma kinase (ALK) inhibitor, and is used for the treatment of ALK gene rearrangement non-small cell lung cancer patients. As it acts on the Crizotinib-resistant patients as well, and can reduce the brain metastases significantly, this drug was granted the status of “breakthrough therapeutic drug” by FDA of America in September 2013, and permitted to come to the market in July 2014 in Japan.
The chemical name of Alectinib is: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-o-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (I), and its structural formula is:

The PCT patents WO2010143664 and WO2012023597 of the original research & development Company and such documents as Page 1271-1280, Volume 20, Bioorganic & Medicinal Chemistry, 2012 and Page 6286-6294, Volume 54, J. Med. Chem., 2011 all have reported the synthetic methods of Alectinib. Its preparation mainly has two synthetic routes.
The first route takes 7-methoxyl-3,4-dihydronaphthalene-2(1H)-ketone (1) as the starting materials, and goes through the bis-methylation reaction (step 1), the 6-bromo reaction (step 2) and the cyclization reaction of hydrazine (step 3) to obtain the intermediate, 6,6-dimethyl-8-methoxyl-9-bromo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (4) (step 4). Then, the intermediate 4 goes through methoxylhy drolysis (step 5), trifluoromethanesulfonic acid esterification (step 6) and condensation with the piperidin ring to obtain the intermediate, 6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-9-bromo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (7) (step 7); the intermediate 7 goes through coupling reaction with (triisopropylsilicyl) acetylene under the actions of palladium catalyst, 2-dicyclohexylphosphin-2,4,6-triisopropylbiphenyl ligands and cesium carbonate etc. to generate the alkyne derivative (8); then the compound 8 will be reduced to ethyl by the alkynyl to obtain the target compound, Alectinib (I).

The second route obtains the intermediate (11) through condensation of 3-iodo-4-ethyltertbutylbenzene (9) with malonic acid mono-tert-butyl ester (10) (Step 1), and then the intermediate goes through condensation reaction with 3-nitrobenzonitrile to obtain the 3-carboxyindolee derivative (12) (Step 2); the intermediate 12 goes through iodination reaction with the 4-morpholinepiperidin through the iodine to obtain the intermediate (13) (Step 3); then the intermediate goes through carboxyl hydrolysis (Step 4) and cyclization reaction (Step 5) to obtain the target compound, Alectinib (I).

Through analysis of the above two synthetic routes, formation step of the core indolee ring adopts condensation of hydrazine and carbonyl (Step 3 in route I) or condensation of nitro (amino after reduction) and carbonyl (Step 2 in route II) respectively. As the two substrates contain multiple functional groups such as halogen, carbonyl, carboxyl, amino and cyano, the reaction process is fairly complicated with increased side reactions and purification difficulty; besides, most of the reaction materials and intermediates are difficult to get. Therefore, with respect to the defects of the current processes, developing a simple and direct, economic and environment-friendly preparation technology with high quality, particularly seeking a process technology that is adaptable to the industrialized production, is of great realistic significance to the improvement of the drug's economic and social benefits.